title: Piperlongumine induces autophagy by targeting p38 signaling.
abstract: Piperlongumine (PL), a natural product isolated from the plant species Piper longum L., can selectively induce apoptotic cell death in cancer cells by targeting the stress response to reactive oxygen species (ROS). Here we show that PL induces cell death in the presence of benzyloxycarbonylvalyl-alanyl-aspartic acid (O-methyl)-fluoro-methylketone (zVAD-fmk), a pan-apoptotic inhibitor, and in the presence of necrostatin-1, a necrotic inhibitor. Instead PL-induced cell death can be suppressed by 3-methyladenine, an autophagy inhibitor, and substantially attenuated in cells lacking the autophagy-related 5 (Atg5) gene. We further show that PL enhances autophagy activity without blocking autophagy flux. Application of N-acetyl-cysteine, an antioxidant, markedly reduces PL-induced autophagy and cell death, suggesting an essential role for intracellular ROS in PL-induced autophagy. Furthermore, PL stimulates the activation of p38 protein kinase through ROS-induced stress response and p38 signaling is necessary for the action of PL as SB203580, a p38 inhibitor, or dominant-negative p38 can effectively reduce PL-mediated autophagy. Thus, we have characterized a new mechanism for PL-induced cell death through the ROS-p38 pathway. Our findings support the therapeutic potential of PL by triggering autophagic cell death.
authors.affiliation: Division of Hematology and Oncology, Comprehensive Cancer Center, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: J-W
authors.initials: JW
authors.lastname: Wang
authors.forename: X
authors.initials: X
authors.lastname: Xiao
authors.forename: Y
authors.initials: Y
authors.lastname: Shan
authors.forename: B
authors.initials: B
authors.lastname: Xue
authors.forename: G
authors.initials: G
authors.lastname: Jiang
authors.forename: Q
authors.initials: Q
authors.lastname: He
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: H-G
authors.initials: HG
authors.lastname: Xu
authors.forename: R-X
authors.initials: RX
authors.lastname: Zhao
authors.forename: K D
authors.initials: KD
authors.lastname: Werle
authors.forename: R
authors.initials: R
authors.lastname: Cui
authors.forename: J
authors.initials: J
authors.lastname: Liang
authors.forename: Y-L
authors.initials: YL
authors.lastname: Li
authors.forename: Z-X
authors.initials: ZX
authors.lastname: Xu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D002460:Cell Line; D004148:Dioxolanes / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D009336:Necrosis; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D017382:Reactive Oxygen Species / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010881:Piperidones
chemical_list: D004148:Dioxolanes; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases; C498077:piperlongumine; D010881:Piperidones